1. Components of the olfactory chemosensory signaling system have previously been found outside of the olfactory epithelium. Using immunohistochemistry we have confirmed that adenylyl cyclase 3 (AC3) and the universal olfactory g protein (Golf ) are expressed in the kidney cortex as well as in the renal medulla. The cortical Golf labeling was associated with the distal convoluted tubule (DCT) as shown by colocalization in serial sections with the NaCl cotransporter NCC, a highly specific marker of the DCT. Golf staining also co-localized with calbindin indicating that it is expressed along the connecting tubule and collecting duct. There was no Golf staining in the thick ascending limb. The localization of AC3 in the kidney had a pattern of expression very similar to that of Golf. AC3 clearly stained distal tubules typically along the apical surfaces of the tubular epithelial cells, and it showed colocalization with NCC in serial sections, but not with a marker of the thick ascending limb. Interestingly, Golf and AC3 were also expressed in the macula densa (MD), a location that was confirmed by overlap with NADPH diaphorase staining, a positive marker of macula densa cells on account of the very specific expression of NO synthase in these cells. The localization of AC3 in macula densa cells suggested that the olfactory system may play a role in specific macula densa functions such as control of vascular tone through the tubuloglomerular feedback mechanism and renin secretion. To assess the TGF profile in wild type and AC3-deficient mice, we performed micropuncture experiments in which the flow rate in the distal segment of a nephron was manipulated while the proximal stop-flow pressure (PSF) in that same nephron was measured as an index of glomerular capillary pressure. Under these experimental conditions TGF response magnitude was not measurably different between wild type and AC3&#8722;/&#8722;mice. Furthermore, flow rates inducing half-maximal responses were statistically indistinguishable between genotypes (9.6 nL/min in wild type and 9.5 nL/min in AC3&#8722;/&#8722;mice). Arterial blood pressure at the time of micropuncture was similar between wild type and AC3&#8722;/&#8722;mice. On the other hand, plasma levels of renin in conscious AC3+/+ and AC3&#8722;/&#8722;mice were about 50% lower in AC3&#8722;/&#8722;mice as compared with those found in their wild type littermates. Thus, although the presence of AC3 and Golf remains highly intriguing their functional role is not entirely clear. 2. The renin-angiotensin system plays a critical role in the maintenance of body salt balance by regulating blood pressure and NaCl excretion by the kidneys. It is therefore not surprising that renin secretion and subsequently plasma renin concentration are changing when NaCl intake changes. In a very predictable manner renin secretion falls in states of NaCl excess and it increases when NaCl intake falls. Despite this well established phenomenon the mechanisms responsible for salt-induced regulation of renin secretion are still unclear. Since the changes in body fluid volume resulting from alterations in NaCl intake lead to changes in sympathetic renal nerve activity and since it is known that renal sympathetic nerves exert pronounced effects on renin secretion through adrenergic -receptors, we assessed the role of -adrenergic receptors in salt-dependent regulation of renin release by determining the effect of salt intake on plasma renin concentration (PRC, ng Ang I/ml hr) and renin mRNA in conscious wild type and 1/2-adrenergic receptor-deficient mice (1/2 ADR-/-). Plasma renin concentration was determined in tail vein blood as measure of renin secretion. On a control diet, plasma renin concentration (ng AngI/ml hr) was significantly higher in wild type than 1/2 ADR-/- mice (1338395 vs. 30448;p=.04). Plasma renin concentration of mice kept on a low Na diet (.003%) for one week increased significantly in both wild type and 1/2 ADR-/- mice (to 2789555 and 73354 respectively). Similarly, a high Na diet (8%) suppressed PRC in both genotypes (to 676213 in wild type, and to 8524 in 1/2 ADR-/-). In additional studies we observed that during inhibition of macula densa NaCl transport by furosemide plasma renin increased in both wild type and 1/2 ADR-/- mice (to 70841073 and to 3277154 respectively). The increment of plasma renin caused by furosemide was augmented by a low Na diet and diminished by a high Na diet in both wild type and 1/2 ADR-/- mice. These data indicate that renin synthesis and release under basal conditions is markedly dependent upon the presence of beta-adrenergic receptors, that the modulating effect of salt intake is maintained in the absence of beta-adrenergic receptors, and that the stimulatory effect of furosemide is maintained in the absence of beta-adrenergic receptors. Thus, it appears that regulation of renin release by salt diet and furosemide is dominated by regulatory inputs other than the sympathetic nervous system. 3. Angiotensin II has long been known to inhibit renin secretion, an outcome thought to be mediated by angiotensin II receptors (AT1a) on the renin-secreting juxtaglomerular cells and termed short feedback loop inhibition of renin release. Conversely, the logical explanation for the stimulatory effect of angiotensin II converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) has been escape from short loop feedback inhibition by angiotensin II. The renin-inhibitory effect of angiotensin II at the cellular level is mediated by the increase in cytosolic calcium caused by stimulation of the Gq-coupled AT1 receptor implying that ACEI and ARB may work through reductions in cell Ca. In the current experiments we examined the hypothesis that angiotensin II blockade acts predominantly through Gs-mediated stimulation of adenylyl cyclase (AC) by testing the effect of ACEI and ARB in mice with juxtaglomerular cell-specific deficiency in the AC-stimulatory Gs generated by conditional knockout of a floxed Gs gene with cre recombinase driven by the endogenous renin promoter. This mouse model has previously been used to selectively delete Gs from JG cells. The ACEI captopril and quinaprilate, and the ARB candesartan significantly increased plasma renin concentration (PRC) to 20-40 times basal plasma renin in wild type mice, but did not significantly alter plasma renin in Gs-deficient mice. In mice fed a low NaCl diet (0.03%) for 7 days and receiving the ACE inhibitor enalapril via the drinking water, plasma renin increased 35 fold (n=12, p<0.001) in wild type mice, whereas it did not change significantly in the Gs-deficient animals (n=12, p=0.17). Pharmacological inhibition of adenylyl cyclase with three different inhibitors reduced the stimulatory effect of captopril by 70-80%. We conclude that the stimulatory effects of angiotensin II blockade on renin synthesis and release are for the most part indirectly mediated by the action of ligand(s) that utilize Gs -dependent pathways.